Activation of TRIM37 by ATF6 and degradation of ACSL4: inhibiting ferroptosis and propelling cervical cancer progression.

BACKGROUND

Cervical cancer (CC), a prevalent gynecological malignancy, shows high global incidence and mortality. Tripartite motif-containing 37 (TRIM37), a significant ubiquitinating enzyme, is overexpressed in CC, fueling its progression, but its role in ferroptosis here is unknown.

METHODS

TRIM37 expression in CC tissues was first predicted using bioinformatics software. Then, RT-qPCR and Western blot were utilized to confirm TRIM37 expression in CC tissues and cells. Subsequently, cellular behaviors were examined by EdU, flow cytometry, and Transwell assay. Besides, ferroptosis-related indicators were detected by using corresponding kits. The dual luciferase reporter assay was conducted to identify the binding between TRIM37 and Activating Transcription Factor 6 (ATF6). Additionally, the Co-IP assay was applied to validate the interaction between TRIM37 and Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4). Finally, the functions of TRIM37 in vivo were investigated by establishing a xenograft tumor model.

RESULTS

TRIM37 expression was increased in CC tissues and cells. Silencing TRIM37 suppressed cell malignant behaviors and promoted ferroptosis. ATF6 activated TRIM37 transcription, with TRIM37 upregulation counteracting ATF6 knockdown effects. TRIM37 degraded ACSL4, and silencing ACSL4 reversed TRIM37 knockdown effects. TRIM37 overexpression counteracted ATF6 knockdown's impact on tumor growth in vivo.

CONCLUSION

ATF6 regulated the expression of TRIM37, which in turn promoted the ubiquitination and degradation of ACSL4, facilitating the progression of CC.